Selective nutrients, such as amino acids are recommended at specified daily dosage to sustain healthy function of bodily systems. The term nutraceutical was coined in the early 1990s by Stephen de Felice, founder and chairman of the Foundation for Innovation in Medicine, to define a food or part of a food including compounds found in food and dietary supplements in food dosage forms that have a health benefit. Further of his assertions though, including the prevention and treatment of disease are unacceptable by the various regulatory health authorities.
Agmatine as a Dietary Ingredient:
Agmatine [(NH2(CH2)4NH2C(NH═)NH], a metabolite of the amino acid arginine, was discovered by Albrecht Kossel in 1910. It is a naturally occurring molecule ubiquitously found in nature, which is biosynthesized by decarboxylation of the amino acid arginine (itself a dietary ingredient), thus known as decarboxylated arginine (see Raasch W, et al., J Pharmacol, (2001) 133:755-780, for comprehensive summary). Agmatine is found in low amounts in many foodstuff derived from plants, fish, with levels as-high-as 200 to 650 mg/kg found in certain fish, and animal products. Importantly, normal agmatine fecal concentrations are the highest among amines, at 14.42 μmol/g dry weight. Microbial production of agmatine, therefore, is considered important source for absorption of agmatine into the body by the mucosal lining of the large intestine (Haenisch B, et al., Am J Physiol Gastrointest Liver Physiol, (2008) November; 295(5): G1104-10).
Agmatine Effects on Bodily Systems:
Ample evidence from laboratory animal studies indicates that treatment with agmatine exerts beneficial health promoting effects on various tissues and bodily functions including mild antihypertensive, cardioprotective and nephroprotective effects. Of specific interest, is the substantial body of evidence demonstrating the beneficial effects of agmatine on the nervous system. These include neuroprotection (Gilad G M, et al., Life Sci, (1995) 58:PL41-PL46; Gilad G M and Gilad V H, Neurosci Lett, (2000) 296:97-100; Gilad G M and Gilad V H, U.S. Pat. No. 5,677,349, Oct. 14, 1997), neuropathic pain-reducing effects (Fairbanks C A et al., U.S. Pat. No. 6,150,419, Nov. 21, 2000), anticonvulsive effects, and anti-anxiety and anti-depressive effects (Fiori L M and Turecki G, J Psychiatry Neurosci (2008) 33:102-10). Enhanced glucose metabolism associated with increased insulin release, and reduced catecholamine release associated with mild reduction in blood pressure and heart rate, are additional beneficial effects of agmatine that may be contributory to its salutary effects on the nervous system. Furthermore, while agmatine biosynthesis (by arginine decarboxylation) in the nervous system is normally very low, it is greatly increased in response to injury (Raasch W, et al., J Pharmacol, (2001) 133:755-780 (p. 764)), thus further implicating agmatine in neuroprotection. Additionally, while agmatine was long known to stimulate proliferation of certain blood born cell types (e.g., thymocytes and lymphocytes), it was found to be a cytotactic compound, preventing cell proliferation of various other cell types (including endothelial cells and astrocytes, as well as various cancer cells) (Gilad G M, et al., Life Sci, (1995) 58:PL41-PL46; Regunathan S and Reis D J, U.S. Pat. No. 5,574,059, Nov. 12, 1996; Fahl W E and Kink J, U.S. Pat. No. 7,045,550, May 16, 2006). Several other patents cover topical (not enteric) application of agmatine for wound healing and cytotactic anti-proliferation effects and therefore, are not related to this application (Raisfeld I H, U.S. Pat. No. 4,507,321, Mar. 26, 1985; Wohlrab J, International Publication No. WO/2003/092668, November 143, 2003; Oblong J E, et al., International Publication No. WO/2004/078157, Sep. 16, 2004).
Agmatine Absorption, Distribution, and Metabolism:
Animal studies demonstrated that agmatine is absorbed by the gastrointestinal tract and distributed in the body, and that it crosses the blood-brain barrier (Haenisch B, et al., Am J Physiol Gastrointest Liver Physiol, (2008) November; 295(5):G1104-10), for comprehensive summary). In the intestinal tract, agmatine can exert diamine oxidase inhibition, which may lead to increased histamine and thus may be unwanted, but at the same time it can lead to favorable accumulation of polyamines, known growth factors of intestinal mucosa. In the body, agmatine is principally metabolized into urea, a known dietary ingredient in ruminant feed, and putrescine, the diamine precursor of polyamines, which are essential for cell growth and viability in general and specifically so for neuroprotection. Otherwise, agmatine can be oxidized and secreted by the kidneys, but this is probably negligible. Agmatine can moderately increase glomerular filtration rate and natriuresis (increased sodium excretion), which may be desired or unwanted depending on health status. Additionally, it can increase gastric acid secretion, which may increase incidence of stress-induced ulcers in laboratory rats. No toxic effects, however, were observed in several species including mice, rats, dogs, calves and monkeys during or after oral intake of agmatine at a variable dose ranges and regimens (see Example II). Taken together, the evidence indicates that dietary agmatine can be considered safe at a daily dose range of about 200-500 mg/kg/day in small animals (e.g., rats and mice) and at lower doses in larger animals with corresponding lower metabolic rates (e.g., up to about 20-80 mg/kg/day in dogs and 10-40 mg/kg/day in horses).
Agmatine Mechanisms of Action:
The cytoprotective mechanism of agmatine action—defined as mechanism promoting cellular resilience and cell survival capabilities—is postulated to be multifunctional. Laboratory studies with experimental animals implicate agmatine in a range of molecular targets important for cytoprotection (Raasch W, et al., J Pharmacol, (2001) 133:755-780). These include: modulation of several neurotransmitter receptors and receptor ionophores (e.g., nicotine, NMDA, imidazoline, and alpha 2-adrenoceptors); blockage of key ionic channels (e.g., ATP-sensitive K+ channels and voltage-gated Ca++ channels); inhibition of nitric oxide (NO) synthase and thus, reduced NO production; inhibition of protein ADP-ribosylation and thus, interfering with cell signaling; inhibition of matrix metalloproteases (MMPs), enzymes implicated in nerve cell death and neuropathic pain; and, inhibition of advanced glycation end (AGE)-product formation, which is a process involved in the pathology of diabetes and neurodegenerative diseases (Lubec G, U.S. Pat. No. 5,077,313, Dec. 31, 1991). The above outlined cytoprotective mechanisms attributed to agmatine underlie its neuroprotective, cardioprotective, nephroprotective, and glycemic control (sometime referred to as glucoprotective) effects. Agmatine acts at multiple molecular targets involved in promoting healthy bodily functions.
Agmatine as a Nutraceutical Cytoprotective Dietary Ingredient:
Although the above references disclose that many of the effects, mechanisms, and metabolism of agmatine are known, the prior art is devoid of any references that disclose that agmatine may be used as a fortifying measure adding to tissue resilience against future insults, thus presenting a beneficial cytoprotective nutraceutical supplement to the diet of a human or animal. However, there are references that disclose what levels of agmatine would be safe to consume and that agmatine may be a beneficial ingredient to a topical application, as discussed above, or for treatment of specific existing disorders. For example, the long known mild hypoglycemic effects of agmatine in experimental animal studies (Raasch W, et al., J Pharmacol, (2001) 133:755-780) and earlier reports on its oral use in diabetics in Oskar Minkowski's clinic in Breslau, Germany, already in the late 1920s (Kleiner I S, Clin. Chem., (1959) 5:79), are evidence for its safety and efficacy as a dietary ingredient by promoting normal glucose metabolism, thus providing glucoprotection in diabetes. Moreover, in humans, agmatine is present in the mucus secreting cells of the stomach and is postulated to play role in acid protection of the stomach, (i.e., gastroprotective effect) (Steer H, Anat Rec, (2009) 292:79-86). Furthermore, a recent clinical study demonstrated safety and suggested efficacy of dietary agmatine in degenerative lumbar spine disorders causing nerve root compression (this report did not disclose agmatine by name: Keynan O, Gilad V H, Dekel S, Gilad G M, An open label phase I dose escalating, non randomized study to assess the safety of a food supplement in patients with lumbar radiculopathy, Israel Spine Soc 8th Ann Meet (Abst), Eilat, Israel, 2007), thus indicating its neuroprotective effects in human. Furthermore, several internet sites (e.g., Man Sports BLUEPRINT http://www.discountanabolics.com/p/MF-006) tout agmatine containing supplements at dose ranges of up to 1 grams per day for body building. However, as will be discussed below in the Description of the Present Invention and in Examples I-III, it is disclosed for the first time that agmatine can be safely taken in the diet at an unpredictably high daily dose range of 1.780-3.560 grams as a long-term regimen (years). Furthermore, agmatine is now disclosed for the first time as an efficacious cytoprotective measure when used to fortify the diet as an ingredient in dietary supplements prior to bodily trauma.
The prior art is silent regarding dietary supplements, nutraceuticals, medical foods, and processed food compositions containing agmatine as a dietary ingredient at the indicated high, long-term daily dosage of 1.780-3.560 grams, or for providing preventive cytoprotection. Importantly, this stands in obvious contrast to the proposed pharmaceutical uses of agmatine as a drug treatment for various preexisting conditions, some of which are discussed herein.
The present invention, therefore, provides effective, useful, and novel nutraceuticals, dietary supplements, medical foods, and food compositions incorporating an effective high dosage amount of agmatine, and nutraceutical acceptable salts thereof as a safe and long-term daily measure for preventive cytoprotection, such as defined by Mueller C. (Nutrition 15:249-251, 1999). Accordingly, the essence of the present invention is cytoprotective high dosage amount of dietary agmatine as a safe preventive measure directed at promoting cellular resilience and cell survival capabilities. This newly discovered usage of dietary agmatine could not have been anticipated or predicted and was not previously taught, suggested, or disclosed by the prior art. Thus, the present invention fills a need not currently available in the market place.
Citation of any document herein is not intended as an admission that such document is pertinent prior art, or considered material to the patentability of any claim of the present application. Any statement as to content or a date of any document is based on the information available to the applicants at the time of filing and does not constitute an admission as to the correctness of such a statement.